NEW ANTIINFLAMMATORY STEROIDS - [16-ALPHA,17-ALPHA-D]-3'-HYDROXYIMINOFORMYL ISOXAZOLINE DERIVATIVES OF PREDNISOLONE AND 9-ALPHA-FLUOROPREDNISOLONE

In a continuing effort to increase the local to systemic activity rati o (L/S) of antiinflammatory agents, a series of new steroids, 11 beta, 21-dihydroxy-3,20-dioxo-1,4-pregnadieno [16 alpha, 17 alpha-d]-3'-hydr oxyiminoformyl isoxazoline (4a), 9 alpha-fluoro-11 beta,21-dihydroxy-3 ,20-dioxo-1 ,4-pregnadieno[16 alpha, 17 alpha-d]-3'-hydroxyiminoformyl isoxazoline (5a), and their 21-acetate derivatives, 4b and 5b, were s ynthesized and evaluated. The topical anti-inflammatory activities of these steroidal drugs were assessed in the croton oil-induced ear edem a bioassay. In the ear edema bioassay, all compounds resulted in dose- dependent inhibition of edema. From these dose-response profiles, the following ED50 values were calculated: 230, 73, 251 and 88 mu g for pr ednisolone (P), 4b, 5a and 5b, respectively. Calculated relative poten cies, setting hydrocortisone (HC) = 1.0, were P, 2.2; 4b, 8.6; 5a, 2.6 and 5b, 7.4. All the new compounds displayed a higher local to system ic activity ratio than P. Results of the five day rat croton oil ear e dema bioassay indicated that only the parent compound P displayed sign ificant suppressive effects on normal body weight gain, corticosterone levels, adrenal and thymus weights. No significant suppressive effect s were observed for any of the new compounds. Results obtained from th is study suggest that the fusion of 3'-hydroxyiminoformyl isoxazoline ring to the C-16/C-17 positions and fluorination at the 9 alpha-positi on of the corticosteroid molecule enhance topical antiinflammatory act ivity without inducing significant adverse systemic effects.